Monoallelic Heb/Tcf12 Deletion Reduces the Requirement for NOTCH1 Hyperactivation in T-Cell Acute Lymphoblastic Leukemia
Early T-cell development is precisely controlled by E proteins, that indistinguishably include HEB/TCF12 and E2A/TCF3 transcription factors, together with NOTCH1 and pre-T cell receptor (TCR) signalling. Importantly, perturbations of early T-cell regulatory networks are implicated in leukemogenesis....
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Frontiers Media S.A.
2022-03-01
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| Series: | Frontiers in Immunology |
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| Online Access: | https://www.frontiersin.org/articles/10.3389/fimmu.2022.867443/full |
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| author | Diogo F. T. Veiga Diogo F. T. Veiga Mathieu Tremblay Bastien Gerby Bastien Gerby Sabine Herblot Sabine Herblot André Haman Patrick Gendron Sébastien Lemieux Sébastien Lemieux Juan Carlos Zúñiga-Pflücker Josée Hébert Josée Hébert Josée Hébert Josée Hébert Joseph Paul Cohen Joseph Paul Cohen Trang Hoang |
| author_facet | Diogo F. T. Veiga Diogo F. T. Veiga Mathieu Tremblay Bastien Gerby Bastien Gerby Sabine Herblot Sabine Herblot André Haman Patrick Gendron Sébastien Lemieux Sébastien Lemieux Juan Carlos Zúñiga-Pflücker Josée Hébert Josée Hébert Josée Hébert Josée Hébert Joseph Paul Cohen Joseph Paul Cohen Trang Hoang |
| author_sort | Diogo F. T. Veiga |
| collection | DOAJ |
| description | Early T-cell development is precisely controlled by E proteins, that indistinguishably include HEB/TCF12 and E2A/TCF3 transcription factors, together with NOTCH1 and pre-T cell receptor (TCR) signalling. Importantly, perturbations of early T-cell regulatory networks are implicated in leukemogenesis. NOTCH1 gain of function mutations invariably lead to T-cell acute lymphoblastic leukemia (T-ALL), whereas inhibition of E proteins accelerates leukemogenesis. Thus, NOTCH1, pre-TCR, E2A and HEB functions are intertwined, but how these pathways contribute individually or synergistically to leukemogenesis remain to be documented. To directly address these questions, we leveraged Cd3e-deficient mice in which pre-TCR signaling and progression through β-selection is abrogated to dissect and decouple the roles of pre-TCR, NOTCH1, E2A and HEB in SCL/TAL1-induced T-ALL, via the use of Notch1 gain of function transgenic (Notch1ICtg) and Tcf12+/- or Tcf3+/- heterozygote mice. As a result, we now provide evidence that both HEB and E2A restrain cell proliferation at the β-selection checkpoint while the clonal expansion of SCL-LMO1-induced pre-leukemic stem cells in T-ALL is uniquely dependent on Tcf12 gene dosage. At the molecular level, HEB protein levels are decreased via proteasomal degradation at the leukemic stage, pointing to a reversible loss of function mechanism. Moreover, in SCL-LMO1-induced T-ALL, loss of one Tcf12 allele is sufficient to bypass pre-TCR signaling which is required for Notch1 gain of function mutations and for progression to T-ALL. In contrast, Tcf12 monoallelic deletion does not accelerate Notch1IC-induced T-ALL, indicating that Tcf12 and Notch1 operate in the same pathway. Finally, we identify a tumor suppressor gene set downstream of HEB, exhibiting significantly lower expression levels in pediatric T-ALL compared to B-ALL and brain cancer samples, the three most frequent pediatric cancers. In summary, our results indicate a tumor suppressor function of HEB/TCF12 in T-ALL to mitigate cell proliferation controlled by NOTCH1 in pre-leukemic stem cells and prevent NOTCH1-driven progression to T-ALL. |
| first_indexed | 2024-12-13T07:57:17Z |
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| issn | 1664-3224 |
| language | English |
| last_indexed | 2024-12-13T07:57:17Z |
| publishDate | 2022-03-01 |
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| series | Frontiers in Immunology |
| spelling | doaj.art-f03cd79bc764496da7d5dad1fdaa2f3b2022-12-21T23:54:31ZengFrontiers Media S.A.Frontiers in Immunology1664-32242022-03-011310.3389/fimmu.2022.867443867443Monoallelic Heb/Tcf12 Deletion Reduces the Requirement for NOTCH1 Hyperactivation in T-Cell Acute Lymphoblastic LeukemiaDiogo F. T. Veiga0Diogo F. T. Veiga1Mathieu Tremblay2Bastien Gerby3Bastien Gerby4Sabine Herblot5Sabine Herblot6André Haman7Patrick Gendron8Sébastien Lemieux9Sébastien Lemieux10Juan Carlos Zúñiga-Pflücker11Josée Hébert12Josée Hébert13Josée Hébert14Josée Hébert15Joseph Paul Cohen16Joseph Paul Cohen17Trang Hoang18Department of Pharmacology and Physiology, Université de Montréal, Institute for Research in Immunology and Cancer, QC, CanadaDepartment of Translational Medicine, School of Medical Sciences, University of Campinas, Campinas, BrazilDepartment of Pharmacology and Physiology, Université de Montréal, Institute for Research in Immunology and Cancer, QC, CanadaDepartment of Pharmacology and Physiology, Université de Montréal, Institute for Research in Immunology and Cancer, QC, CanadaCentre de Recherches en Cancérologie de Toulouse (CRCT), Université de Toulouse, Institut National de la Santé et de la Recherche Médicale (INSERM), UMR-1037, Université Toulouse III Paul Sabatier (UPS), Toulouse, FranceDepartment of Pharmacology and Physiology, Université de Montréal, Institute for Research in Immunology and Cancer, QC, CanadaUnité de recherche en hémato-oncologie Charles-Bruneau, Centre de Recherche du CHU Sainte-Justine, Montréal, CanadaDepartment of Pharmacology and Physiology, Université de Montréal, Institute for Research in Immunology and Cancer, QC, CanadaDepartment of Pharmacology and Physiology, Université de Montréal, Institute for Research in Immunology and Cancer, QC, CanadaDepartment of Pharmacology and Physiology, Université de Montréal, Institute for Research in Immunology and Cancer, QC, CanadaDepartment of Biochemistry and Molecular Medicine, Institute for Research in Immunology and Cancer, Université de Montréal, Montréal, QC, CanadaDepartment of Immunology, University of Toronto, and Sunnybrook Research Institute, Toronto, ON, CanadaDepartment of Pharmacology and Physiology, Université de Montréal, Institute for Research in Immunology and Cancer, QC, CanadaInstitut universitaire d’hémato-oncologie et de thérapie cellulaire, Hôpital Maisonneuve-Rosemont, Montréal, QC, CanadaQuebec Leukemia Cell Bank, Centre de recherche de l’Hôpital Maisonneuve-Rosemont, Montréal, QC, CanadaDepartment of Medicine, Université de Montréal, Montréal, QC, Canada0Department of Computer Science and Operations Research, Université de Montréal, Montreal, QC, Canada1Université de Montréal, Montreal, QC, CanadaDepartment of Pharmacology and Physiology, Université de Montréal, Institute for Research in Immunology and Cancer, QC, CanadaEarly T-cell development is precisely controlled by E proteins, that indistinguishably include HEB/TCF12 and E2A/TCF3 transcription factors, together with NOTCH1 and pre-T cell receptor (TCR) signalling. Importantly, perturbations of early T-cell regulatory networks are implicated in leukemogenesis. NOTCH1 gain of function mutations invariably lead to T-cell acute lymphoblastic leukemia (T-ALL), whereas inhibition of E proteins accelerates leukemogenesis. Thus, NOTCH1, pre-TCR, E2A and HEB functions are intertwined, but how these pathways contribute individually or synergistically to leukemogenesis remain to be documented. To directly address these questions, we leveraged Cd3e-deficient mice in which pre-TCR signaling and progression through β-selection is abrogated to dissect and decouple the roles of pre-TCR, NOTCH1, E2A and HEB in SCL/TAL1-induced T-ALL, via the use of Notch1 gain of function transgenic (Notch1ICtg) and Tcf12+/- or Tcf3+/- heterozygote mice. As a result, we now provide evidence that both HEB and E2A restrain cell proliferation at the β-selection checkpoint while the clonal expansion of SCL-LMO1-induced pre-leukemic stem cells in T-ALL is uniquely dependent on Tcf12 gene dosage. At the molecular level, HEB protein levels are decreased via proteasomal degradation at the leukemic stage, pointing to a reversible loss of function mechanism. Moreover, in SCL-LMO1-induced T-ALL, loss of one Tcf12 allele is sufficient to bypass pre-TCR signaling which is required for Notch1 gain of function mutations and for progression to T-ALL. In contrast, Tcf12 monoallelic deletion does not accelerate Notch1IC-induced T-ALL, indicating that Tcf12 and Notch1 operate in the same pathway. Finally, we identify a tumor suppressor gene set downstream of HEB, exhibiting significantly lower expression levels in pediatric T-ALL compared to B-ALL and brain cancer samples, the three most frequent pediatric cancers. In summary, our results indicate a tumor suppressor function of HEB/TCF12 in T-ALL to mitigate cell proliferation controlled by NOTCH1 in pre-leukemic stem cells and prevent NOTCH1-driven progression to T-ALL.https://www.frontiersin.org/articles/10.3389/fimmu.2022.867443/fullSCL/TAL1LMO1HEB/TCF12E2A/TCF3NOTCH1T-cell acute lymphoblastic leukemia |
| spellingShingle | Diogo F. T. Veiga Diogo F. T. Veiga Mathieu Tremblay Bastien Gerby Bastien Gerby Sabine Herblot Sabine Herblot André Haman Patrick Gendron Sébastien Lemieux Sébastien Lemieux Juan Carlos Zúñiga-Pflücker Josée Hébert Josée Hébert Josée Hébert Josée Hébert Joseph Paul Cohen Joseph Paul Cohen Trang Hoang Monoallelic Heb/Tcf12 Deletion Reduces the Requirement for NOTCH1 Hyperactivation in T-Cell Acute Lymphoblastic Leukemia Frontiers in Immunology SCL/TAL1 LMO1 HEB/TCF12 E2A/TCF3 NOTCH1 T-cell acute lymphoblastic leukemia |
| title | Monoallelic Heb/Tcf12 Deletion Reduces the Requirement for NOTCH1 Hyperactivation in T-Cell Acute Lymphoblastic Leukemia |
| title_full | Monoallelic Heb/Tcf12 Deletion Reduces the Requirement for NOTCH1 Hyperactivation in T-Cell Acute Lymphoblastic Leukemia |
| title_fullStr | Monoallelic Heb/Tcf12 Deletion Reduces the Requirement for NOTCH1 Hyperactivation in T-Cell Acute Lymphoblastic Leukemia |
| title_full_unstemmed | Monoallelic Heb/Tcf12 Deletion Reduces the Requirement for NOTCH1 Hyperactivation in T-Cell Acute Lymphoblastic Leukemia |
| title_short | Monoallelic Heb/Tcf12 Deletion Reduces the Requirement for NOTCH1 Hyperactivation in T-Cell Acute Lymphoblastic Leukemia |
| title_sort | monoallelic heb tcf12 deletion reduces the requirement for notch1 hyperactivation in t cell acute lymphoblastic leukemia |
| topic | SCL/TAL1 LMO1 HEB/TCF12 E2A/TCF3 NOTCH1 T-cell acute lymphoblastic leukemia |
| url | https://www.frontiersin.org/articles/10.3389/fimmu.2022.867443/full |
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